Hard capsules are widely used in the pharmaceutical field as oral dosage forms for administration to humans and animals of, e.g., pharmaceuticals, veterinary products, and food and dietary supplements. Hard capsules have advantages compared to other conventional dosage forms including better patient compliance, greater flexibility in dosage form design, and less expensive manufacturing processes. Pharmaceutical capsules are conventionally divided into soft shell capsules (hereinafter soft capsules) and hard shell capsules (hereinafter hard capsules).
For many pharmaceutical and/or health and nutrition applications, e.g., when active ingredients are to be administered, it is often desirable that the substances to be encapsulated are pre-mixed with at least one excipient to form a composition which is then filled into capsules. The resulting combination of active ingredient with at least one excipient must be compatible with the capsule shell in that it must not affect the capsule shell stability after filling. Typical compatibility issues that may arise are impairment of the mechanical properties of the capsule shells resulting, e.g., in leaks and/or softening of the shells and/or impairment of the chemical properties of the capsule shells, including but not limited to modification of the capsule shell dissolution profile.
Hard capsules are often commercially preferable over soft capsules since they have a simpler manufacturing process (i.e., hard capsule shells are manufactured separately and empty while the active ingredient and formulation fill can be formulated in a separate step), more flexibility in the filling step(s), and easier equipment operability as compared to soft capsules. For these reasons, it would be desirable that a liquid fill be compatible with hard capsules. Hard capsule shells may be manufactured with a variety of polymeric substances such as gelatin, hydroxypropyl methyl cellulose (HPMC), and pullulan, as well as mixtures thereof. The liquid fill must be compatible with the hard capsule shell polymeric substance selected, and not every liquid fill is compatible with every hard shell capsule shell.
While gelatin capsules are readily available and are often utilized, gelatin capsules containing certain moisture levels may lose plasticity and may show serious deterioration in impact resistance. A desire for animal-product free vegetarian capsules has resulted in an interest in non-gelatin based hard capsules. Plant-based hard capsules, such as HPMC capsules and pullulan capsules, prepared without gelatin, are of particular interest. Additionally, certain active ingredients, particularly liquid fills, interact deleteriously with gelatin while cellulose derivatives such as HPMC may be less reactive with certain active ingredients and with certain liquid fills, particularly hygroscopic or reactive active ingredients.
HPMC capsules include VCAPS® hypromellose capsules and VCAPS® Plus hypromellose capsules available from Capsugel. HPMC capsules have low moisture content, are vegetarian, and have low cross-linking. Pullulan capsules include PLANTCAPS® capsules available from Capsugel.
It is also desirable that the fill be liquid, since this facilitates capsule filling step as well as gastro-intestinal release and absorption of the substance(s) after capsule shell disintegration. In particular, for a liquid active ingredient, a liquid fill is desirable if it is stable in the capsule shell chosen.
It is also desirable that the liquid fill be not visually opaque or milky since this has been linked to lower patient compliance.
It is also desirable that the liquid fill and/or the excipients chosen be compatible with the active ingredient(s) and/or substances intended to be pre-mixed with it. Typically, instability can result in oxidation and/or hydrolysis over time of the active ingredients mixed in the liquid fill.
The carboxylic acid, β-hydroxy-β-methylbutyric acid or HMB, is an active metabolite of the branched-chain amino acid leucine. Endogenous production in humans is in small amounts (Nissen S L, Abumrad N N, Nutritional role of the leucine metabolite β-hydroxy-β-methylbutyrate (HMB). J Nutr Biochem. 1997; 8:300-11). Activity of HMB in humans and other mammals is reported to include reducing blood cholesterol and low-density lipoprotein levels, promoting nitrogen retention, increasing lean tissue development, enhancing the immune response, combating disease associated wasting, and increasing the aerobic capacity of muscle without increase in muscle mass, among other effects. See, e.g., U.S. Patent Application Publication No. 2012/0053240; Hasselgren P-O, β-hydroxy-β-methylbutyrate (HMB) and prevention of muscle wasting, Metabolism Clinical and Experimental (2013), in press. In its acid form, the compound is called 3-hydroxy-3-methylbutyric acid, β-hydroxy-β-methylbutyric acid, or β-hydroxy-isovalaryic acid, and can be designated “HMB free acid.” The structural formula for HMB free acid is (CH3)2C(OH)CH2COOH.
U.S. Patent Application Publication No. 2012/0053240 to Rathmacher et al. discloses methods of administering HMB free acid, and solids, tablets, capsules, and liquids generally, and discloses that HMB free acid because it is a liquid is much more difficult to deliver or incorporate into products, particularly unit dosage forms. Further, the HMB free acid has the impurity 3,3-dimethyl acrylic acid with a very off flavor which is difficult to mask. For these reasons, nearly all dosage forms to date have utilized the calcium salt in crystalline powder form, despite the lowered biological effectiveness of the salt compared to the free acid. Biological testing has been performed with the salt form for muscle quality compared to placebo (Experimental Gerontology 48 (2013) 1303-1310). Because HMB free acid is a liquid at room temperature, a tablet form containing HMB free acid would not be physically compatible and thus could not be readily manufactured. While administration of HMB free acid in the form of gels or as an additive in nutritional food products (including liquids) is possible, such administration is less palatable and less convenient for the patient compared to capsules, leading to lower patient compliance. Pure HMB free acid in gel form is not compatible with hard capsules. A stable hard capsule unit dosage form of the HMB free acid is therefore desirable and would result in greater patient compliance and a reduced need for taste masking agents. Lack of such a hard capsule unit dosage form has hindered testing of HMB free acid.
U.S. Pat. No. 8,217,077 to Baxter et al. discloses methods of stimulating new protein synthesis in patients affected by disease-associated wasting conditions by treatment with β-hydroxy-β-methylbutyric acid formulated as a solid, crystalline salt form into capsules or dissolved in water. Baxter did not distinguish between the crystalline salt form and the liquid free acid of HMB.
U.S. Pat. Nos. 6,294,192 and 6,451,339, and European Patent Applications EP1158959A and EP1210063A disclose compositions comprising a liquid carrier for the administration of hydrophilic or hydrophobic active agents. Generally, the carriers are comprised of one hydrophilic surfactant and one hydrophobic surfactant, the former being in greater amount. These documents disclose huge lists of ingredients that can be variably combined to obtain equally effective carriers for liquid fills. No data are provided to infer stability of hard capsule shells after filling with liquid fills, or deleterious effects of liquid active ingredients, on hard capsule integrity.
U.S. Pat. No. 5,919,481 discloses carriers for the administration of substances (including hydrophobic ones) prone to human abuse. The aim of these carriers is to reduce the risk of drug abuse. Accordingly, these carriers must be highly viscous at room temperature so that they cannot be freely removed with a syringe. Additionally, no data are provided regarding stability of any hard capsule shells in case these carriers had to be filled into hard capsules.
Thus, an object of the present disclosure is to provide a physically stable, liquid filled hard capsule comprising HMB free acid and at least one excipient. Further objects are to provide a liquid filled hard capsule that has a liquid fill which is clear at room temperature and that is compatible with the substances that are mixed with it before being filled into hard capsule shells, in particular to provide a stable, liquid filled hard capsule containing the active ingredient beta-hydroxy-beta-methylbutyric acid, either alone or in combination with other active ingredient(s).